Project Summary Our understanding of neuropsychiatric disorders is undergoing a paradigm shift away from simple models emphasizing neurotransmitter imbalance towards more sophisticated theories based on abnormalities in neural circuit function. This is especially important for understanding disorders like Schizophrenia and PTSD, which defy simple biochemical explanations, but are now known to involve abnormal patterns of neural ensemble activity. Even for other types of brain disorders such as neurodegenerative disorders (e.g. Parkinson's Disease), or neurodevelopmental disorders (e.g. Autism) that have molecular-genetic, cellular or environmental causes, there is increasing awareness that the dysfunction is ultimately expressed at the level of neural circuits in the brain, and manifests in abnormal neural circuit dynamics. However, we still lack crucial basic understanding of neural activity patterns during normal behavior and how these patterns are altered in disease. Many rodent models of human brain diseases are now available, but neuroscientists are still hindered by lack of a technology for large-scale recording and manipulation of activity in large populations of genetically identified neurons in the brains of behaving animal subjects. Inscopix, Inc. was spun out of Stanford University to commercialize a miniature fluorescence microscope technology to enable neuroscientists to visualize Ca2+ dynamics in up to 1200 neurons simultaneously in awake, behaving rodents at cellular resolution. The development of the commercial system, nVista, was partly funded by a prior NIMH SBIR grant. The project surpassed all expectations and exemplifies how the NIH/NIMH SBIR program is highly effective in catalyzing innovation and supporting commercialization of breakthrough innovations for Neuroscience. The outcome of the prior SBIR Phase I and Phase II is an nVista system that is today in use at over 200 laboratories around the world and that has led to >50 scientific publications in top-tier journals. In this Fast-Track proposal, we will build on the prior successful SBIR and the success of nVista, and develop and commercialize a next generation brain mapping platform that transforms nVista into a versatile platform integrating single- and dual-color imaging, volumetric imaging, and optogenetics stimulation capabilities, together with web-based, cloud-compatible data acquisition and control. In Phase I, we will design and fabricate prototypes of the new microscope for the next generation brain mapping platform (Aim 1) together with an advanced video data acquisition and processing system (Aim 2). We will validate performance of these prototypes and conduct the first in vivo experiments with a small group of beta labs (Aim 3). In Phase II, we will fabricate 15 complete, user-friendly systems, incorporating feedback from Phase I (Aim 4), with supporting image processing and analysis algorithms (Aim 5). We will perform extensive in vivo experiments with a larger set of beta sites to demonstrate the scientific value of all features (Aim 6). At the end of Phase II, we will have a new miniature microscope system that integrates single- and dual-color imaging, volumetric imaging, and optogenetics stimulation capabilities, together with web-based data acquisition and control ready for mass production and commercialization to the Neuroscience community. The new product will obsolete our current nVista and will become our flagship product enabling brain researchers around the world to causally link neural circuit activity to brain function. We expect the new product to catalyze neural circuit research and to become a centerpiece of worldwide efforts to map brain circuit activity and to understand the brain in action. We also expect the product to be broadly adopted by large research centers and by Pharma, expanding the range of applications beyond basic Neuroscience to translational projects built around understanding brain disease and developing next generation treatments.